Identification of novel small molecule non-peptidomimetic inhibitor for prolyl oligopeptidase through in silico and in vitro approaches. Issue 5 (23rd March 2020)

• Record Type: Journal Article
• Authors: Shrivastava, Apeksha; Srivastava, Shubham; Malik, Ruchi; Alam, M. Mumtaz; Shaqiquzamman, M.; Akhter, Mymoona
• Is Part Of: Journal of biomolecular structure & dynamics. Volume 38:Issue 5(2020)
• Page Start: 1292
• Page End: 1305
• Publication Date: 2020-03-23
• Subjects: ADME -- BEDROC -- MM/GBSA -- molecular dynamics simulation -- prolyl oligopeptidase assay -- structure-based virtual screening -- Youden index; Biomolecules -- Periodicals; Molecular structure -- Periodicals; Molecular Biology -- Periodicals; Biomechanics -- Periodicals; 572
• DOI: 10.1080/07391102.2019.1602078
• Languages: English
• ISSNs: 0739-1102

Abstract

Abstract: Prolyl oligopeptidase (POP) enzyme has been studied for various disorders, viz. Schizophrenia, Alzheimer's, Parkinson's, Depression, Inflammation, etc., for three decades, but no drug has passed through the clinical trials, possibly because of indigent pharmacokinetics. This might have been a result of similar structures of drug candidates. This study aimed at identifying novel small non-peptidomimetic inhibitors for POP enzyme that could serve as a lead for developing newer drugs. Structure-based virtual screening of molecules of MolMall database was conducted on the POP enzyme (PDB ID 3DDU) to identify potential hits. The hits identified were subjected to computational pharmacokinetic screening followed by molecular mechanics/generalized Born and surface area studies to estimate the binding free energy of the docked complexes. After that, nine hits were selected and tested for POP inhibitory activity, among which one compound MM 4 was found to be most potent with EC50 of 100 µM. Compound MM 4 was further subjected to molecular dynamics simulations to study the overall stability of the ligand–protein complex. The compound interacted strongly with catalytic amino acid Arg643 by forming salt and water bridges; it also interacted well with amino acids Phe173, Arg252 and Met235. This study provides a lead molecule for further development of POP inhibitors. Communicated by Ramaswamy H. Sarma